ABSTRACT: The proposed studies build upon CRISP1, a five-year study of chronic rhinosinusitis (CRS) in a cohort of 7847 subjects, representative of the general population in central Pennsylvania, across the full spectrum of CRS. CRISP1 included the first U.S. longitudinal studies of chronic nasal and sinus symptoms and sinus inflammation by CT scan in the general population. We made novel observations regarding CRS symptom and CT patterns; risks associated with CRS; and sex differences. To improve CRS prevention, diagnosis, and management, studies are now needed to identify the presence of inflammation earlier in the disease than is detected by CT; identify phenotypic and endotypic patterns associated with outcomes; identify risk of longer- term outcomes; and further evaluate sex differences. We will combine CRISP1 data with longitudinal EHR data and new prospective data collection in five separate studies to address four specific aims. In Specific Aim 1 we will develop new approaches to CRS phenotyping. We hypothesize that patterns of longitudinal symptoms, medical history, and CT scan findings will identify new CRS phenotypes that are associated with natural history and long-term outcomes. This aim will be addressed across several of our studies, including by re-contacting CRISP1 participants. Specific Aim 2 will evaluate if CRS endotypes, defined with NLF biomarkers, are associated with phenotype, natural history, and outcomes. For this aim, two studies will be completed. In the first, 450 subjects will be enrolled, have a baseline sinus CT scan and NLF sampling and followed for 18 months with questionnaires, another NLF sample, and linkage to EHR data. In the second, we will conduct a study in parallel with Northwestern to measure NLF biomarkers in 50 subjects each with CRS alone, CRS with asthma, and CRS with bronchiectasis. Our data will be combined with those from a similar study at Northwestern, enabling us to evaluate the impact of setting (general population vs. tertiary care) on findings. Specific Aim 3 is to evaluate CRS as a risk factor for other diseases. We hypothesize that CRS subgroups will be differentially associated with increased risk for development of asthma and bronchiectasis. For this aim, we will conduct an EHR-based CRS retrospective cohort study of 10,000 subjects with sinus CT evidence of CRS and 20,000 persons without; and a bronchiectasis case-control study of 1000 persons with chest CT evidence of bronchiectasis and 4000 controls without. These studies will evaluate associations of CRS phenotypes and severity with risk of development of asthma and bronchiectasis. Specific Aim 4 will evaluate sex differences. We hypothesize that associations among endotypes, phenotypes, natural history, and longer-term outcomes will differ by sex. Sex differences will be evaluated in all five studies. The proposed research continues our novel collaborative work focused on measurement of CRS symptoms, inflammation, co-morbidities, and natural history, linked to longitudinal EHR data, for up to 15-20 years of total observation time, in ways that should advance understanding, diagnosis, and management of CRS across the full spectrum of disease.